The principal objective of the proposed research is to develop a fundamental understanding of the effects of autonomic agents, cyclic nucleotides and antiinflammatory drugs on the biologic functions of human neutrophils. Two functions of neutrophils will be studied; namely, lysosomal enzyme secretion from and phagocytosis by purified human neutrophils in the presence of particulate immune reactants. Data from our laboratory indicate that catecholamines, such as epinephrine, and cyclic AMP inhibit whereas cholinergic agents, such as acetylcholine, and cyclic GMP enhance the immunologic secretion of lysosomal enzymes from, and particle ingestion by, human neutrophils. Cyclic GMP accumulation is associated with enzyme release provoked by immune reactants and acetylcholine, whereas cyclic AMP accumulation is associated with the inhibition of neutrophil function by epinephrine. Thus, it appears that intracellular cyclic nucleotides may play a role in the bioregulation of neutrophil function. Studies are in progress to elucidate the precise role of extracellular calcium in our cell model of stimulus-secretion coupling. Further, the enzyme system responsible for cyclic GMP synthesis, guanylate cyclase, is being characterized in detail in both neutrophils and lymphocytes. Finally, the mechanisms by which certain glucocorticosteroids inhibit neutrophil function (earlier studies from this laboratory), with particular emphasis on cyclic nucleotide metabolism, will be explored in detail. The proposed research, as well as the work completed, should contribute to the achievement of the objective of these studies, which is to better understand the biologic factors regulating human neutrophil function.